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Sodium Thiosulfate Injection, USP, 25%

Briefing Document
for
The Pediatric Subcommittee of the
Oncologic Drugs Advisory Committee
01 November 2011
Adherex Technologies Inc.
PO Box 13628
68 T.W. Alexander Drive
Research Triangle Park, NC 27709
USA

26 September 2011

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

Sodium Thiosulfate Injection, USP, 25%


Briefing Document Pediatric Subcommittee of ODAC

26 September 2011

TABLE OF CONTENTS

TABLE OF CONTENTS ....................................................................................................................................... 2


1

INTRODUCTION AND RATIONALE FOR THE DEVELOPMENT OF SODIUM


THIOSULFATE ............................................................................................................................................ 4

REGULATORY HISTORY OF SODIUM THIOSULFATE........................................................................ 6

NONCLINICAL EXPERIENCE WITH SODIUM THIOSULFATE ........................................................... 8


3.1
3.2
3.3
3.4

OVERALL CLINICAL DEVELOPMENT PLAN...................................................................................... 12


4.1
4.2
4.3
4.4
4.5
4.6
4.7

4.8

Preclinical Studies with STS to Prevent Ototoxicity ......................................................................... 8


Lack of STS Tumor Protection in Rodents and Cells In Vitro .......................................................... 9
Pharmacokinetics of STS ................................................................................................................ 10
Confirming the Lack of Tumor Protection of Delayed Administration of Sodium
Thiosulfate in Animals .................................................................................................................... 10
Background and Preliminary Dose and Regimen Selection............................................................ 12
Clinical Signs and Symptoms of Cisplatin Induced Ototoxicity ..................................................... 13
Diagnosis and Measurement of Ototoxicity: The Brock Grading System ...................................... 13
Pharmacokinetics in Humans .......................................................................................................... 14
4.4.1
STS Administered as a Single Agent ............................................................................ 14
4.4.2
STS Administered in Combination with Platinum Agents ............................................ 15
Summary of Phase I and Phase II Clinical Experience ................................................................... 16
Safety in Humans ............................................................................................................................ 18
4.6.1
Adverse Events.............................................................................................................. 18
Phase III Clinical Program .............................................................................................................. 20
4.7.1
Study ACCL0431, A Randomized Phase III Study of Sodium
Thiosulfate for the Prevention of Cisplatin-Induced Ototoxicity in
Children. ........................................................................................................................ 20
4.7.2
SIOPEL 6, A Multicentre Open Label Randomised Phase III Trial of
the Efficacy of Sodium Thiosulphate in Reducing Ototoxicity in
Patients Receiving Cisplatin Chemotherapy for Standard Risk
Hepatoblastoma. ............................................................................................................ 21
Accelerated Approval and Phase IV Program ................................................................................. 22
4.8.1
Accelerated Approval .................................................................................................... 22
4.8.2
Phase IV ........................................................................................................................ 22

CHALLENGES IN THE DEVELOPMENT OF SODIUM THIOSULFATE ............................................ 25


5.1

Issues Concerning an Adult Cancer Trial to Determine a Tumor Protection Effect of


Sodium Thiosulfate ......................................................................................................................... 25

CONCLUSION ............................................................................................................................................ 30

REFERENCES ............................................................................................................................................ 32

ATTACHMENTS ........................................................................................................................................ 37

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LIST OF IN-TEXT TABLES


Table 4-1.
Table 4-2.
Table 4-3.
Table 4-4.
Table 5-1.

Clinical Experience with STS ....................................................................................... 17


Effect of STS on Serum Sodium ................................................................................... 18
Pediatric Adverse Events Frequency ............................................................................. 19
Phase IV Prospective Cohort Study Sample Size and Number of
Events ............................................................................................................................ 23
Sample Size Calculations (N per Arm) for Non-Inferiority Study
of Cisplatin-Containing Regimen .................................................................................. 27

LIST OF IN-TEXT FIGURES


Figure 3-1.
Figure 3-2.
Figure 3-3.
Figure 3-4.

STS Protects Against Cisplatin Ototoxicity in Rats ........................................................ 8


Carboplatin-Treated Nude Rats ....................................................................................... 9
Cisplatin-Treated DAOY Medulloblastoma Cells ........................................................ 10
Cisplatin-Treated SMS-SAN Neuroblastoma Xenografts ............................................. 10

LIST OF ATTACHMENTS
Attachment 1.
Attachment 2.

Comparison of SIOPEL 6 and COG ACCL0431


Sample Size Calculations for Non Inferiority Study of Cisplatincontaining Regimen With/Without STS

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Briefing Document Pediatric Subcommittee of ODAC

26 September 2011

INTRODUCTION AND RATIONALE FOR THE DEVELOPMENT


OF SODIUM THIOSULFATE

Adherex welcomes the opportunity to discuss with the Pediatric Subcommittee of the
Oncologic Drugs Advisory Committee the development of Sodium Thiosulfate Injection,
USP, 25%, for the prevention of ototoxicity induced by platinum cancer chemotherapy in
pediatric patients.
Since the approval of cisplatin over 30 years ago, platinum compounds have been an integral
component of cancer chemotherapy regimens. Platinum compounds are approved and used to
treat a multitude of different cancers in adult and pediatric patients.1
Ototoxicity is a significant complication of cisplatin and other platinum-based chemotherapy
compounds. According to the American Cancer Society Facts and Figures 2010,2
10,700 cases of childhood cancers may occur among children ages 014 in 2010.
Approximately 2000 of these children will receive platinum based-chemotherapy. More than
40% of these children will develop significant and irreversible damage to hearing following
treatment with cisplatin.3
Sodium thiosulfate (STS) is a water-soluble thiol compound and acts as a chemical reducing
agent. It is FDA approved for the treatment of cyanide poisoning and has been used in
oncology to prevent cisplatin nephrotoxicity and as an antidote for extravasation of various
chemotherapy agents. Delayed administration (48 h) of high dose STS (1620 g/m2)
protects against platinum-induced ototoxicity in animal models4,5,6,7 and in patients.8,9,10 The
mechanism by which STS reduces nephrotoxicity and ototoxicity is not fully understood but
may involve free radical scavenging and/or covalent binding to inactivate the platinum
compound. STS reacts irreversibly with cisplatin to form Pt(S2O3)4. Although the precise
mechanism by which STS interferes with cisplatin antitumor activity is not known, the
antioxidant properties of STS contravene the alkylation properties of platinum agents. As
such, STS would be inactive against antineoplastic agents that act via enzyme inhibition, cell
signaling or regulation, microtubule formation, and immunologic recognition.
STS may also protect against nephrotoxicity by reducing exposure of the kidneys to platinum
by neutralizing cisplatin in the kidneys where STS is highly concentrated. Following IV
injection, STS is distributed throughout the extracellular fluid. Some STS is converted to
sulfate in the liver and up to 95% is excreted unchanged in the urine. The terminal half-life
is approximately 3 hours. The plasma half-life and clearance of cisplatin are not affected by
STS.
Ototoxicity from platinum-based chemotherapy may result from deposition of protein-bound
platinum in the inner ear. Although free platinum, the chemical species active against
cancer, has largely disappeared from the circulation four hours after administration in guinea
pigs4 and in rats5, protection by STS effectively prevented platinum-associated hearing loss
when STS administration was delayed up to eight hours after administration of platinumbased treatment. This establishes that the action of STS to prevent ototoxicity occurs later

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than that of platinum against the target cancer cell. It is thought that hearing loss caused by
platinum compounds result from the deposition of protein-bound platinum in the cochlea
and STS binds platinum/protein complexes thereby minimizing their toxicity. The anticancer activity of cisplatin manifest during the first two hours after administration when
unbound cisplatin distributes into cancer cells.11 Importantly, because STS does not cross
cell membranes8,12 it cannot react with the platinum-DNA complex that has already formed
within tumor cells. With delayed administration of STS six hours after cisplatin dosing, the
antitumor activity is not affected by STS. However, STS is still able to prevent hearing loss
because this beneficial process appears to occur at a later time, in a different location, and
through interactions with platinum metabolites not involved in platinum anti-cancer activity.
At a bolus dose of 20 g/m2 over 15 minutes, STS has sufficient high plasma concentrations to
rapidly, covalently bind to any residual extracellular cisplatin and thereby prevent
ototoxicity. Because STS is to be administered six hours after cisplatin, antitumor efficacy of
cisplatin would not be compromised.

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REGULATORY HISTORY OF SODIUM THIOSULFATE

STS has an established clinical safety profile from use as an antidote for cyanide poisoning
and nitroprusside overdose. The US Army received approval for STS as an antidote to
cyanide poisoning in February 1992 under New Drug Application 20-166.
STS has received orphan drug designation (ODD) in the US for the prevention of ototoxicity
induced by platinum cancer chemotherapy in pediatric patients. The cancers being studied in
the two ongoing Phase III studies are very rare, although the burden of ototoxicity is
disproportionate among affected children due to the efficacy of cisplatin in these diseases.
The incidence of liver cancer in children less than 14 years of age is 2.4/105, with
hepatoblastoma having the highest incidence (2.0/105).13 Hepatoblastoma occurs most
frequently in infants or very young children between the ages of 2 months and 3 years.14
The incidence of hepatocellular carcinoma is negligible in children less than 14 years of
age. Overall survival for patients with standard risk hepatoblastoma is 95%15 but only
25% for children with hepatocellular carcinoma.13 Approximately 100150 new cases of
pediatric liver cancer are diagnosed in the US per year.16
The incidence of extracranial germ cell tumors (GCT) for males aged 04 years was
7/106 and 31/106 for males aged 1519 years.17 The corresponding incidences for
females were 5.8/106 and 25.3/106, respectively. During the interval 19752002, 5-year
survival in children with GCTs increased from 89% to 98% in children less than 15 years
of age and from 70% to 95% in children 1519 years of age.17 Approximately 900 new
cases of germ cell tumors in children less than 20 years of age are diagnosed each year.16
An analysis in North America gave the incidence of pediatric neuroblastoma to be
27.75/106 in children aged 04 years and 10.95/106 in children aged 014 years.18 The
overall survival rate was 55%. There are approximately 650 new cases of neuroblastoma
diagnosed in the US annually of which 450 cases are advanced and require cisplatin
therapy. Ototoxicity in neuroblastoma is noted to be severe Brock grade 3 or 4 in 25
54% of children depending on the treatment regimen.19,20
The incidence of medulloblastoma is approximately 1.52.0/105 with approximately
350 new cases each year.21 Cranial radiation, which is also used for treatment increases
the incidence and severity of cisplatin-induced hearing loss. With aggressive surgery,
craniospinal radiotherapy, and chemotherapy, 5-year survival maybe greater than 50%.
Using current treatments, 80%90% of patients without disseminated disease can be
cured.22 In a single center series, Brock grade 1 or more ototoxicity was found in 72% of
patients treated as compared to 14% for those treated for low grade glioma.23
The incidence of osteogenic sarcoma in children less than 15 years of age is 25.6/106
with 450600 new cases/year in the US.24 Overall 10-year survival is estimated at
59.8%.25
Cisplatin is also used for other, less common malignancies that occur in children,
e.g., nasopharyngeal carcinoma and for salvage treatment for many other malignancies,
including rhabdomyosarcoma.

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On 08 March 2011, Adherex and the FDA met to review the clinical development program
for STS. FDA observed that based on its mechanism of action, STS may reduce the
anticancer activity of platinum-containing compounds. Adherex would need to convincingly
demonstrate that STS does not reduce the efficacy of cisplatin. If data are not convincing,
non-inferiority trials would be required. Because the number of patients required for
non-inferiority studies cannot be achieved in the pediatric setting, the Agency advised that
the non-inferiority study could be conducted in adults.
Subsequently, Adherex was invited to the Pediatric Subcommittee of the Oncology Drug
Advisory Committee to discuss the clinical trial program. We are challenged to meet the
obligation of proving lack of tumor protection with STS by an adult non-inferiority trial and
look forward to the guidance of the Advisory Committee.

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3
3.1

26 September 2011

NONCLINICAL EXPERIENCE WITH SODIUM THIOSULFATE


Preclinical Studies with STS to Prevent Ototoxicity

STS is a water-soluble thiol compound with antioxidant properties and is commercially


available as an antidote for acute cyanide poisoning. When given intravenously, STS is
rapidly excreted by the kidney.
Initial studies used a guinea pig model in which carboplatin and cisplatin were ototoxic when
administered with furosemide. Physiological measurements and counts of outer hair cells
showed that STS (11.6 g/m2) was protective against carboplatin-induced cochlear damage
when administered 2, 4, or even 8 hours after carboplatin. STS was also protective against
cisplatin in the guinea pig, blocking 4050 dB threshold shifts at frequencies between 4 and
32 kHz. In another guinea pig study, the maximum tolerated dose of cisplatin and overall
survival were increased by STS due to lower platinum-related toxicity.12 In a rat model of
platinum ototoxicity, cisplatin (68 mg/kg) was delivered to the vertebral arteries via a
retrograde right external carotid artery infusion to the aorta. Auditory brainstem responses
(ABR) taken 5 days after cisplatin administration demonstrated 20 dB change in threshold
at 416 kHz (Figure 3-1). To evaluate delayed STS otoprotection, a dose of STS (8 g/m2)
was used that provided equivalent serum thiol concentration as that achieved in patients
given 20 g/m2. When STS was administered at 4 or 8 hours after cisplatin, significant
hearing protection was achieved at every frequency (Figure 3-1, Panels A and B), whereas no
significant otoprotection was found when STS administration was delayed to 12 hours after
cisplatin (Figure 3-1, Panel C).5
Figure 3-1.

STS Protects Against Cisplatin Ototoxicity in Rats

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3.2

26 September 2011

Lack of STS Tumor Protection in Rodents and Cells In Vitro

With respect to tumor protection, STS at a dose of 8 mg/kg given 8 hours after
carboplatin/etoposide in a rat subcutaneous tumor model had no significant impact on
chemotherapy efficacy.6 The time to tumor progression (8.1 0.7 days) was not
significantly different from chemotherapy alone (8.9 0.6 days, n = 18, p = 0.188). In
another model7 nude rats (8 per group) with intracerebral human lung carcinoma xenografts
were treated with a carboplatin three drug regimen delivered intra-arterially with osmotic
blood-brain barrier (BBB) disruption. There was no difference in tumor volume between the
groups that received chemotherapy, whether or not they also received STS at 4 and 8 hours
(Figure 3-2).
Figure 3-2.

Carboplatin-Treated Nude Rats

Tumor protection was also modeled with cells in vitro. Dickey et al reported no tumor
protection by STS for DAOY medulloblastoma cells co-cultured in vitro with cisplatin and
then exposed to STS after 6 hours (Figure 3-3).5
Finally, Harned et al treated nude mice with SMS-SAN neuroblastoma xenografts with
cisplatin 4 mg/kg/day intraperitoneally for 4 days compared with untreated controls. STS
administered (3.5 mg/kg/day) concurrently with cisplatin appeared to block the anti-tumor
activity. However, delay of STS until 6 hours after cisplatin administration did not affect
anti-tumor activity of cisplatin (Figure 3-4).11 Thus, there is reasonable evidence in
preclinical studies of tumors that include pediatric malignancies that STS does not cause
tumor protection when administered 6 to 8 hours following the cisplatin dose.

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Figure 3-3.

Cisplatin-Treated DAOY Medulloblastoma Cells

Figure 3-4.

Cisplatin-Treated SMS-SAN Neuroblastoma Xenografts

3.3

Pharmacokinetics of STS

The pharmacokinetics of STS have been studied in animals and suggests that the binding of
STS to platinum occurs in the systemic circulation where it was shown to decrease renal
toxicity in rats.26
3.4

Confirming the Lack of Tumor Protection of Delayed Administration of Sodium


Thiosulfate in Animals

Current and delayed administration of STS with cisplatin have been evaluated against human
neuroblastoma xenograft cell lines in a Severe Combined Immuno Deficiency (S.C.I.D.)
mouse model.11 When STS was administered 6 hours after the administration of cisplatin,
STS did not compromise the antineoplastic activity of cisplatin. STS did abrogate the
antitumor affect when co-administered with cisplatin.

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Precedence for alternatives to large human clinical studies has been established under the
FDA regulation known as "the Animal Rule" (21 CFR 314.600). The Guidance for Industry
published with the Animal Rule states when it is neither ethical nor feasible to conduct
human efficacy studies, FDA may grant marketing approval based on adequate and wellcontrolled animal studies when they establish that the drug is reasonably likely to produce
clinical benefit in humans.27 This rule was established for biological warfare purposes.
However Adherex believes a reasonably large animal study to confirm the lack of tumor
protection from STS when given 6 hours after cisplatin administration is worth consideration.
The study could include tumor types that affect children. In vivo and in vitro models with
analogous tumors established a tumor protection effect when cisplatin and STS were given
simultaneously. Repeating these experiments with both concurrent and delayed dosing of
STS would provide reassurance that delayed administration of STS dose not inhibit tumor
activity of cisplatin.
Study design and numbers of animals could be defined if such an approach was deemed
reasonable but could include cohorts of: Vehicle Control; Cisplatin alone; Cisplatin + STS
given immediately after cisplatin; Cisplatin + STS administered 6 hours after cisplatin.

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OVERALL CLINICAL DEVELOPMENT PLAN

The clinical portion of this document consists of four parts.


Sections 4.14.6 describe the initial development of STS to reduce cisplatin ototoxicity in
pediatric patients.
Section 4.7 describes two ongoing Phase III pediatric trials designed to demonstrate
survival and reduction of ototoxicity in a more robust manner than initial studies. An
update on the progress of these trials is included.
Section 4.8 describes a proposal for accelerated approval and a Phase IV program to
confirm the safety and efficacy of STS.
Section 5 addresses the concept of designing a trial with STS to demonstrate presence or
absence of tumor protection in adult cancer patients treated with a cisplatin-containing
regimen.
4.1

Background and Preliminary Dose and Regimen Selection

Protection against ototoxicity depends on a dose and schedule that can separate the
therapeutic and toxic effects of platinum therapy and allow STS to neutralize metabolites
responsible for toxicity and spare the therapeutic activity of the parent platinum.
Dose selection is based on published studies of effects of delayed administration of STS on
ototoxicity of carboplatin and osmotic blood brain barrier disruption.9,10, 28, 29
A brief description of dose selection based on human pharmacokinetic studies follows:
The standard dose of STS in cyanide poisoning is 12.5 g administered IV as 50 ml of a
250 mg/ml (25%) solution over 10 minutes, which can be repeated at half the original
dose if needed. Thus, in cyanide poisoning the total standard dose of STS is up to
18.75 g (or 11 g/m for an individual with a body surface area of 1.7 m).
STS doses of 4, 8, 12, 16, and 20 g/m administered IV 2 hours after intra-arterial
carboplatin (CBDCA) have been evaluated for safety.28 Mild nausea and/or vomiting
were noted in a few subjects receiving 4 or 8 g/m. Higher doses were administered after
prophylactic administration of droperidol. Transient hypernatremia (10 to 15% increase
over baseline) associated with transient hypertension (10 to 15% increase over baseline)
was noted in subjects receiving 16 or 20 g/m.
STS doses of 4 or 8 g/m administered IV 2 hours after intra-arterial carboplatin did not
protect against ototoxicity compared to a historical control group.28
STS doses of 16 or 20 g/m administered IV 2 hours after carboplatin did protect against
ototoxicity compared to a historical control group.28
Dutch investigators gave STS as one (20 g/m) or two (20 and 16 g/m) 15 minute IV
infusions, depending on the patients baseline hearing status. Patients with impaired
baseline hearing received two doses of STS. STS given at 4 hours or 4 and 8 hours after
carboplatin administration significantly delayed the development of ototoxicity and
decreased the incidence of ototoxicity when compared with the historical control group.30
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The same investigators reported results of a prospective, randomized Phase III trial of
STS as an otoprotectant in patients with head and neck cancer undergoing cisplatin and
radiation therapy.30, 31 The conclusion was that STS did not cause significant change in
disease-free or overall survival compared with patients not receiving STS.30

Studies by Neuwelt9 and Doolittle10 indicate the importance of separating platinum


chemotherapy from thiol chemoprotection by route and timing of administration.
Carboplatin was administered intra-arterially and STS was given intravenously 4 and 8 hours
after the carboplatin at doses as high as 20 mg/m2.
4.2

Clinical Signs and Symptoms of Cisplatin Induced Ototoxicity

Platinum-based ototoxicity occurs in a progressive and dose-dependent manner.32,33


Auditory sequelae include high-frequency sensorineural hearing loss and tinnitus. The
tinnitus sometimes subsides but hearing loss is almost always permanent.34 Hearing loss is
most commonly bilateral, although cases of unilateral hearing impairment are occasionally
reported. High frequency hearing sensitivity is usually affected first because high frequency
regions within the cochlea appear to be more susceptible to cisplatin.35 With continued
exposure to cisplatin, hearing loss tends to increase in severity and progressively spreads to
hearing at lower frequencies that are associated with speech.8 The incidence of ototoxicity
associated with cisplatin and/or carboplatin (myeloablative dosing for stem cell transplant)
ranges from 1% to 100%.33,34,36
Hearing loss profoundly affects the quality of human life. Loss of pure-tone sensitivity in the
2 to 4 kHz frequency range results in difficulty discriminating consonant sounds especially
when attempting to identify words in the presence of background noise. Hearing loss
exceeding the 20 dB hearing level (HL) in speech frequencies impacts family and social
interaction and work status.10
In young children who have received platinum-based therapy, clinical, behavioral and
psychological studies show impaired language acquisition with learning disability and
cognitive dysfunction. In older children, evaluation of educational and behavioral effects
document impaired functional status, cognitive status, depressive symptomatology and
disability.10
The impact of hearing loss in very young children is devastating, since language
development and general learning at that age are critically dependent upon hearing.
4.3

Diagnosis and Measurement of Ototoxicity: The Brock Grading System

Ototoxicity is subjectively experienced as hearing loss and tinnitus resulting from


sensorinueural damage. Irreversible hearing loss, typically in the high frequency range (4 to
8 kHz) and very high frequency range (9 to 20 kHz), may occur as early as the first cisplatin
dose and typically worsens, progressively affecting lower frequencies in a cumulative dosedependent fashion. Symptoms of tinnitus, although not always associated with loss of
hearing, tend to precede measurable decreases in hearing thresholds.37 The hearing loss is
irreversible.
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The two ongoing clinical studies, ACCL0431 and SIOPEL 6, will evaluate hearing loss using
the Brock grading system.
The Brock grading system38 was designed for children to account for the typical slope and
configuration of ototoxic hearing loss. Brock can indicate the expected disability or handicap
according to the frequencies affected and the amount of hearing impairment. Brock also has
predictive value of future hearing loss if additional cisplatin is administered to a patient.
There is a statistically significant relationship between Brock grade and cumulative cisplatin
dose. It can therefore be used by oncologists to make treatment decisions for an individual
patient. The numeric grades below are based on a cut-off threshold level of 40 dB HL at the
frequencies 1, 2, 4 and 8 kHz:
Grade 0 ototoxicity represents hearing thresholds better than the 40 dB HL at all
frequencies 0.25 to 8 kHz. This level of hearing is usually accepted by oncologists as an
acceptable cost of cure for cancer.
Grade 1 hearing loss occurs when thresholds at 8 kHz are greater than or equal to the
40 dB HL.
Grade 2 hearing loss represents thresholds greater than or equal to the 40 dB HL at 4 kHz
and above.
Grade 3 hearing loss represents thresholds greater than or equal to the 40 dB HL at the
frequencies 2 to 8 kHz.
Grade 4 hearing loss represents thresholds greater than or equal to the 40 dB HL at 1 kHz
and above.
Hearing loss at Grades 1, 2, 3, and 4 are considered clinically significant and have potential
impact on communicative and educational development. Depending on alternative
treatments for a particular patient a decision about additional treatment for a child may be
made at these grades. Children with Grade 1 hearing loss should not have difficulty
understanding speech in most listening conditions; however, they will require preferential
classroom seating and educational monitoring. Children with high frequency hearing loss
including 4 kHz (Grade 2) will likely have difficulty hearing and discriminating the high
frequency consonant speech sounds and have difficulty understanding speech in noise or over
distance. They may benefit from amplification or assistive listening devices, such as a
classroom sound field or personal FM system, particularly during the early language-learning
years. Children with hearing loss extending into the frequencies 2 kHz and lower (Grades 3
and 4) will require hearing aids for speech and language development and for
communication.
4.4

Pharmacokinetics in Humans

4.4.1 STS Administered as a Single Agent


In humans, STS is rapidly excreted in the urine. Whatever is not renally excreted is oxidized
to sulfate or incorporated into endogenous sulfur-containing compounds that are normal
metabolic constituents, such as amino acids.37,39

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Neuwelt et al. evaluated the pharmacokinetics of STS in a small cohort of patients given STS
on two consecutive days. Plasma STS values increased in a linear fashion with increasing
dose.9 At the highest dose, 20 g/m2, plasma STS levels were approximately 60% of levels
observed in guinea pigs at a dose of 11 g/m2. The mean plasma and urine STS levels were
similar comparing the values obtained after the same dose of STS given on both Day 1 and
Day 2. Two patients with Blood Brain Barrier Disruption (BBBD), received STS as a 4 g/m2
bolus IV injection followed by a 6-hour slow infusion of 12 g/m2. Cerebrospinal fluid levels
in these two patients at the end of the slow infusion were 7% of the serum concentration of
STS.
4.4.2 STS Administered in Combination with Platinum Agents
Two clinical studies examined the effect of STS on cisplatin pharmacokinetics when the two
agents were administered concurrently. STS was administered concurrently with cisplatin
administered IP40 and IV.41
In the first study, patients received IP cisplatin at doses ranging from 90 to 270 mg/m2.40
STS was administered as an IV bolus at a dose of 7.5 g/m2 at the start of the IP instillation of
cisplatin, and then as a continuous IV infusion of 2.13 g/m2/hour for 12 hours. Non-protein
bound cisplatin was measured in plasma. A dose of 90 mg/m2 administered IP without STS
produced approximately the same systemic exposure as a dose of 100 mg/m2 administered
IV. The plasma half-life and clearance of cisplatin were not affected by STS. While the
cisplatin dose of 90 mg/m2 administered in the absence of STS caused an average increase in
serum creatinine of 55% over pretreatment values, there was no significant increase in serum
creatinine at any dose of cisplatin when STS was administered with concurrent IP
chemotherapy.
In the second study,41 Pfeifle et al. escalated the dose of cisplatin given concurrently with
STS administration until the maximum tolerated dose was reached. Toxicities and
pharmacokinetics were compared to those of a standard dose of 100 mg/m2 cisplatin in the
absence of STS. The combination of cisplatin and STS was administered over a 3-hour
period. During the first hour, STS was administered at a dose of 3.3 g/m2 in conjunction with
oral hydration. The appropriate dose of cisplatin and 6.6 g/m2 STS were then concurrently
administered over the next 2 hours. Pharmacokinetic parameters were examined in seven
courses of treatment with 202 mg/m2 cisplatin with STS and eight courses of treatment with
100 mg/m2 cisplatin without STS. Non-protein-bound cisplatin was measured in plasma.
There were no significant differences in the elimination rate constants, the apparent volume
of distribution, or the total body clearance of cisplatin when administered with or without
STS. In addition, the area under the mean concentration versus time curve and peak plasma
concentration approximately doubled when the cisplatin dose was doubled, suggesting that
plasma concentration of STS was too low to react with cisplatin before the latter was cleared
from the blood. In contrast, the authors do suggest that STS was able to protect against renal
toxicity at the doubled cisplatin dose because STS concentrations were 25-fold higher in the
kidneys than in plasma. Thus, the necessary concentration of STS was present to rapidly
react with the regional cisplatin.

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4.5

26 September 2011

Summary of Phase I and Phase II Clinical Experience

The published clinical experience with STS when used as a cancer chemoprotectant is listed
in Table 4-1. There are 24 studies or case reports that include 1,237 cancer patients. The
study populations ranged from one (a pediatric cisplatin overdose) to 213 patients. The
studies encompassed eight tumor categories including seven studies of head and neck and
three studies each of brain, ovarian, oral, and unspecified multiple cancers.
Study objectives were equally broad and include pharmacokinetics, platinum dose-escalation,
nephrotoxicity or ototoxicity, and therapeutic response. Since most studies were relatively
small and included varied endpoints, a comprehensive summary is not appropriate.
However, results generally were encouraging.
Among the head and neck studies, there were several reports of high rates of therapeutic
response associated with STS co-administration coupled with little or no renal or otologic
toxicities.42,43,44 In a study comparing treatments with cisplatin with or without STS,
therapeutic responses were similar, and no serious renal or otologic toxicities occurred.31 In
a study of malignant brain tumors, it was suggested that STS did not affect tumor response.28
A number of studies successfully achieved the primary objective of increasing the tolerable
dose of cisplatin when STS was added to the regimen. Studies included treatment of
intraperitoneal tumors40,45 oral cancers,46 and solid tumors.47
Reduction of renal and otologic toxicities of cisplatin is a principal reason for developing
STS. In treatments of intraperitoneal tumors39,45 solid tumors47, laryngeal and oral
cancers46,48,49 head and neck cancers31,42,43,44 and brain cancers,9,10,28 treatment with STS
lowered or eliminated these toxicities.

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Table 4-1.

26 September 2011

Clinical Experience with STS

No. Patients

No.
Cycles

STS Doses / Durations

17

38

7.5 g/m2 rapid infusion &


25.56 g/m2 over 12 hrs

CP 90 mg/m2 up to 270 mg/m2

Howell, 198240

24

40

3.3 g/m2 for 1st hr. & 6.6


g/m2 for 2nd and 3rd hr.

CP 180 mg/m2 up to 874 mg/m2

Pfeifle, 198541

131

485

4 g/m2 infusion followed by


12 g/m2 over 6 hrs.

CP 150 mg/m2 up to 225 mg/m2

Markman, 198545

14

17

4 g/m2 infusion followed by


12 g/m2 over 6 hrs.

CP 90 mg/m2 + Etoposide
350 mg/m2

Goel, 198950

36

85

3.3 g/m2 for 1st hr. & 6.6


g/m2 for 2nd and 3rd hr.

CP 150 mg/m2 up to 225 mg/m2

Markman, 199147

11

28

3.3 g/m2 for 1st hr. & 6.6


g/m2 for 2nd and 3rd hr.

CP 200 mg/m2

Reichman, 199151

28

75

4 g/m2 infusion followed by


12 g/m2 over 6 hrs.

CP 180 mg/m2

Kim, 199352

14

Unknown

3 g/m2 bolus followed by 12


g/m2 over 6 hrs.

CP 90 mg/m2

Guastalla, 199453

29

110

9 g/m2 over 3 mins. followed


by 12 g/m2 over 6 hrs.

CP 150 mg/m2 + 180 to 200 cGy/day


x 35 fractions

Robbins, 199454

36

186

3 g/m2 bolus followed by 12


g/m2 over 6 hrs.

CP 90 mg/m2 + Etoposide 600 to


800 mg/m2

De Jong, 199555

23

92

9 g/m2 over 3 mins. followed


by 12 g/m2 over 6 hrs.

CP 150 mg/m2 delivered rapidly


through microcatheters

Los, 199556

42

160

9 g/m2 over 2 hrs. followed


by 12 g/m2 over 12 hrs.

CP 150 mg/m2 + 1.8 to 2.0 Gy/day x


35 fractions

Robbins, 199648

62

Unknown

9 g/m2 rapid infusion

CP 150 mg/m2 x4 weekly + 1.8 to


2.0 Gy/fraction to a total dose of 68
to 74 Gy

Denys, 199757

60

253

9 g/m2 over 3 mins. followed


by 12 g/m2 over 6 hrs.
(simultaneous)

CP 150 mg/m2 x4 weekly + 66 to


74 Gy to primary, 50 Gy to
uninvolved lower neck, at
2.0 Gy/fraction

Robbins, 199742

29

105

4 g/m2 bolus followed by


12 g/m2 over 6 hrs.

CP 200 mg/m2 + Etoposide 350


mg/m2

Van Rijswijk, 199758

29

125

4, 8, 12, 16, 20 g/m2 over 15


min. (first 3-months, 4 g/m2
followed by infusion of
12 g/m2 over 6 hrs) & 8, 12,
16, and 20 g/m2 over 15 min.

Carboplatin 200 mg/m2

Neuwelt, 19989

67

Unknown

9 g/m2 rapid infusion

CP 150 mg/m2 over 5 to 15 mins.

Kovacs, 199946

213

717

9 g/m2 over 30 min. & 12


g/m2 over 12 hrs

CP 150 mg/m2 + 68/72 Gy

Robbins, 200043

41

454

20 g/m2 15 min. bolus & 20


g/m2 + 16 g/m2 15 min. bolus

Carboplatin 200 mg/m2 x 2

Doolittle, 200110

Available for public disclosure without redaction

Chemotherapy / Radiotherapy

Reference

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STS Doses / Durations

26 September 2011

No. Patients

No.
Cycles

Chemotherapy / Radiotherapy

Reference

135

158

9 g/m2 over 15 to 20 min. &


12 g/m2 over 6 hrs.

CP 150 mg/m2 + 180 rad (1.8 Gy) or


200 rad (2 Gy) per fraction to a
planned total of 6600 to 7400 rad (66
to 74 Gy)

Samant, 200144

4 g/m2 infusion followed by


2.7 g/m2/day for 13 days

CP 360 mg/m2 over 72 hrs


(overdose)

Erdlenbruch, 200259

25

90

9 g/m2 over 30 mins. & 12


g/m2 over 6 hrs.

CP 150 mg/m2 weekly + 70 Gy,


2.0 Gy/fraction, daily for 5 days over
7 weeks

Robbins, 200449

12

214

10, 14, 16, or 20 g/m2 post 2


or 4 hrs & 12 or 16 g/m2 post
6 or 8 hrs

Carboplatin 200 mg/m2

Neuwelt, 200629

158

9 g/m2 over 30 mins. & 12 g/


m2 over 2 hrs.

CP 150mg/m2 IA infusion or 100m


mg/m2 IV infusion

Zuur, 200731

CP = cisplatin

4.6

Safety in Humans

4.6.1 Adverse Events


A literature review reveals that adverse events reported as related to STS consist of transient
hypernatremia, transient hypertension, and nausea.
In a study examining the potential of STS to protect against ototoxicity, Neuwelt et al. noted
that transient hypernatremia occurred with the administration of high dose STS (16 and
20 g/m2; n = 17).29 There was no correlation between total dosage of STS and the rise in
serum sodium levels, nor was there any correlation between the dose of carboplatin and
sodium levels. Table 4-2 shows the change in serum sodium in patients who received
different doses of STS.
Table 4-2.
Time after STS
Administration

Effect of STS on Serum Sodium


STS Dose
8 g/m2 (n=3)

12 g/m2 (n=3)

16 g/m2 (n=2)

20 g/m2 (n=3)

Baseline

141

140

136

140

Immediately post

145

146

146

156

15 min post

142

146

144

152

30 min post

144

144

143

150

Source: Reference 29

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26 September 2011

In most patients, the hypernatremia was associated with a transient increase in blood pressure
of 10% to 15% that began midway through the 15-minute infusion and lasted through the
completion of the infusion. The transient increase in blood pressure resolved immediately
after completion of the STS infusion without intervention or sequelae.
Sodium levels were also closely monitored in the 12 children who received delayed STS in
conjunction with carboplatin/BBBD.29 Serum sodium levels were obtained at baseline prior
to each treatment and on the day following each treatment. Grade 2 hypernatremia was
reported in five of 132 courses (3%) and Grade 3 and 4 hypernatremia were reported in three
(1%) and two (1%) courses, respectively. Grade 3 and 4 hypernatremia occurred in one
patient with Fanconis kidney secondary to prior ifosfamide. In general, the hypernatremia
affected very few patients and was considered clinically insignificant in terms of the changes
in serum Na.
Nausea was also reported in patients who received high-dose STS (20 mg/m2).
Premedication with antiemetics was necessary to minimize the nausea. Frequency of adverse
events are shown in Table 4-3. All events occurred immediately within 12 days of receiving
drug.
Table 4-3.

Within 12 days
of receiving drug

Pediatric Adverse Events Frequency


Common
Occasional
Happens to 21100
Happens to 520 children
children out of every 100 out of every 100

Rare
Happens to < 5 children out of
every 100

Transient hypernatremia

Hypotension, contact dermatitis,


irritation if leaks from the vein
during administration

Nausea, vomiting

Source: Reference 29

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4.7

26 September 2011

Phase III Clinical Program

STS is being studied by cooperative groups in two Phase III clinical studies of survival and
reduction of ototoxicity. The studies and current status are briefly described below. A
comparison table of the two studies is provided under Attachment 1.
4.7.1 Study ACCL0431, A Randomized Phase III Study of Sodium Thiosulfate for the
Prevention of Cisplatin-Induced Ototoxicity in Children.
Study ACCL0431 was initiated in June 2008 by the Children's Oncology Group (COG)
primarily at sites in the US and Canada. The study is expected to enroll approximately
135 patients most of whom have diagnoses of one of five childhood cancers typically treated
with intensive cisplatin therapy, including newly diagnosed hepatoblastoma, germ cell tumor,
osteosarcoma, neuroblastoma, and medulloblastoma. Cancer patients whose treatment
regimen includes cisplatin are also eligible (e.g., nasopharyngeal carcinoma), but few such
patients are expected to enroll.
Patients are stratified according to prior cranial radiation (yes vs no), age (< 5 years vs
5 years) and duration of cisplatin infusion (< 2 hours vs 2 hours). Patients are randomized
to 1 of 2 arms (see Attachment 1 for dosing instructions).
Arm 1 (STS): Patients receive STS IV over 15 minutes beginning 6 hours after the
completion of each cisplatin infusion. Treatment with STS continues until the
completion of cisplatin therapy.
Arm 2 (observation): Patients do not receive STS. Patients undergo audiological
assessment at baseline, prior to each course of cisplatin, and then at 4 weeks and 1 year
after the last course of cisplatin or other cancer treatment. Some patients may undergo
saliva collection for DNA studies.
After completion of study, patients are followed periodically for 10 years.
As of 01 September 2011, 110 of the required 135 children were enrolled with expected
completion of enrollment by mid-2012.
Two interim analyses to protect patient safety were part of the study protocol. The first was
to assess and compare early tumor response to chemotherapy between the two study
regimens (STS vs. Observation). In this semi-quantitative analysis involving the first 45
study subjects for whom tumor response data were available, the best response for each
patient as reported by the institution was used to estimate whether there were any striking
differences in treatment failures among the STS-treated patients. The second was to perform
a futility analysis on the efficacy of STS for otoprotection using hearing outcomes data for
approximately 75 patients. The results of these analyses were submitted for review by the
COG Data Safety Monitoring Committee in April 2011. At present, accrual to this study is
ongoing.

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4.7.2 SIOPEL 6, A Multicentre Open Label Randomised Phase III Trial of the
Efficacy of Sodium Thiosulphate in Reducing Ototoxicity in Patients Receiving
Cisplatin Chemotherapy for Standard Risk Hepatoblastoma.
SIOPEL 6 is being conducted by The International Childhood Liver Tumour Strategy Group,
SIOPEL, a group of medical specialists founded in 1987 under the umbrella of the
International Society of Paediatric Oncology (SIOP). The study was initiated in October
2007 and is expected to enroll 102 evaluable patients in up to 33 participating countries. As
of 01 September 2011, 42 children were enrolled.
The SIOPEL trial is being conducted in standard risk hepatoblastoma where the effectiveness
of the platinum treatment is very high, and the trial is being carefully monitored to identify
an excess treatment failure rate.
Trial treatment consists of the following phases (see Attachment 1 for dosing instructions):
Pre-operative randomised 1:1 chemotherapy (4 courses of cisplatin, with or without STS,
every second week)
Surgical removal of all remaining tumour lesions. If surgery has to be delayed, 1 or
2 cycles of the post-operative chemotherapy may be given pre-operatively.
Post-operative chemotherapy (2 courses of cisplatin, with or without STS, every second
week)
Patients with progressive disease after 2 or more courses of cisplatin, with or without
STS, will stop trial treatment
SIOPEL 6 had as a possible secondary objective the influence of STS on cisplatin
pharmacokinetics, an objective clearly unobtainable since STS is administered 6 hours after
cisplatin and well after levels of plasma cisplatin can be measured. As a surrogate for the
presence of cisplatin, cisplatin-DNA adducts are being measured at various times in
peripheral blood cells to determine the extent of cisplatin anti-tumor activity.
The statistical design was established to monitor for an excess relapse or treatment failure
rate comparing Event Free Survival/Overall Survival (EFS/OS) but not to establish noninferiority of the two arms.
In case of concerns of an adverse effect of STS on the short-term efficacy of the cisplatin
chemotherapy, the trial may be stopped early as well. Interim efficacy results on response to
chemotherapy will be evaluated after every 20 patients. The first review has been conducted
by the Independent Data Monitoring Committee (IDMC) and concluded that current cancer
efficacy results do not raise any concerns of impairment of the efficacy of cisplatin related to the
addition of STS.

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4.8

26 September 2011

Accelerated Approval and Phase IV Program

4.8.1 Accelerated Approval


As discussed, full enrollment of 135 patients in the COG ACCL0431 study is expected by
mid-2012.
The COG study would establish with adequate statistical power the effectiveness of STS as
an otoprotectant, the primary objective. Tumor response will be monitored to detect major
differences in tumor response, but the study is not adequately powered for non-inferiority of
event-free survival or overall survival. Equivalence studies would require hundreds of
patients and are not feasible due to a variety of factors essentially related to the low
incidence of relevant childhood cancers.
Should the COG ACCL0431 study results be compelling, Adherex proposes to file the initial
New Drug Application under accelerated approval with the single COG study. All available
safety data from SIOPEL 6 will be included with the initial submission.
Further clinical safety and efficacy data to transition from accelerated to traditional approval
and/or to complete a Risk Evaluation and Mitigation Strategy (REMS) program could be
generated post approval. The post marketing program is described below.
4.8.2 Phase IV
Should the results of the COG ACCL0431 study be sufficiently compelling to warrant filing
for marketing approval, additional data to confirm the safety and efficacy of STS in the postmarketing setting could be obtained from the final results of SIOPEL 6 and a new Phase IV
safety study.
The post marketing Phase IV study could be conducted by COG, which has the infrastructure
and guidelines for long-term follow-up. More than 90% of the children with relevant types
of cancers in the US are treated by COG-affiliated centers.
A potential design of the Phase IV study is given below.
Title:

Prospective Cohort Study of Children Treated with Cisplatin With or


Without STS

Rationale:

This is a non-interventional prospective cohort study to obtain additional


long-term safety follow-up data for children treated with cisplatin (with or
without STS) to confirm that use of STS is not tumor protective (i.e. STS
does not decrease event-free survival (EFS) by at least 10%).

Population:

Eight hundred consecutively enrolled children (118 years of age) with


newly diagnosed malignancies to be treated with cisplatin (with or without
STS/non-randomized or assigned) in any clinical center affiliated with the
Childrens Oncology Group (COG).

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26 September 2011

Study
Evaluations:

Event-free survival (EFS) and overall survival (OS) will be assessed. If the
patient is already enrolled on a therapeutic study, disease evaluations will
be performed at time points specified in that protocol. If the patient is not
enrolled on any therapeutic study, disease evaluations will be performed at
time points deemed to be appropriate by the investigator. Baseline subject
and established prognosis disease characteristics, as well as cisplatin and
STS dose (if used) will also be collected.

Duration of
Follow-up:

Three years from time of enrollment in the study.

Study
Endpoints:

EFS and OS will be compared between STS-treated and non-STS-treated


patients. The statistical analysis will be performed using a Cox
proportional hazard analysis with baseline demographic and prognostic
characteristics, cisplatin dose and STS dose (if used) as explanatory
variables (i.e. covariates) in the model.

Sample Size
and Power:

Table 4-4 shows the total sample size and number of events required to
have 80% power to detect a 10% difference in EFS between patients
treated with and without STS assuming the composite EFS across all tumor
types ranges from 59% to 79%. The weighted EFS (i.e., 59%) was derived
from the current COG protocol based upon the expected proportion of
patients entering the study by tumor type.

Table 4-4.

Phase IV Prospective Cohort Study Sample Size and Number of


Events
0.05

0.05

0.05

0.05

0.05

0.59

0.64

0.69

0.74

0.79

0.49

0.54

0.59

0.64

0.69

0.740

0.724

0.703

0.675

0.635

Power (%)

80

80

80

80

80

Overall N

762

750

720

672

608

Total number of events, E

345

302

253

203

153

2-sided significance level; alpha


Group 1 proportion

Group 2 proportion

2 at

Hazard ratio, h=ln

1)

/ ln

at time t
time t
2)

For example, when the total sample size is 762, with a total number of events required, E, of
345, a 0.050 level two-sided log-rank test for equality of survival curves will have 80%
power to detect the difference between a Group 1 proportion 1 at time t of 0.590 and a
Group 2 proportion 2 at time t of 0.490 (a constant hazard ratio of 0.740); this assumes no
dropouts before time t.

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26 September 2011

Depending on the number of patients with different tumor types, the composite EFS may be
higher than 59% thereby reducing the overall N and total number of events necessary to be
able to detect a 10% difference between STS-treated and non STS-treated patients.

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26 September 2011

CHALLENGES IN THE DEVELOPMENT OF SODIUM


THIOSULFATE

The most important issue for the Advisory Committee is the potential for STS to decrease the
anti-tumor efficacy of cisplatin. Despite the 6-hour interval between the infusion of cisplatin
and the infusion of STS, is the risk serious enough to require a study demonstrating noninferiority of cisplatin and STS versus cisplatin alone before approving STS for use in
ototoxicity prevention in a vulnerable pediatric population?
Due to the large number of patients required for a non-inferiority study, it is not feasible to
conduct a pediatric study. Therefore, would the prospective cohort study described in
Section 4.8.2 be adequate or should a randomized non-inferiority study be conducted in
adults?
5.1

Issues Concerning an Adult Cancer Trial to Determine a Tumor Protection Effect


of Sodium Thiosulfate

For medical, developmental, and societal reasons, avoidance of ototoxicity is critical in


children receiving cancer chemotherapy with cisplatin. The antioxidant STS can prevent the
ototoxicity of cisplatin but also has the potential to reduce antitumor activity. During a
meeting held in March 2011, FDA suggested that a non-inferiority trial in adults might be
necessary to demonstrate that STS is not tumor protective at doses and administration
intervals proposed for pediatric treatment. 60
This section addresses scientific and practical issues related to an adult, non-inferiority tumor
protection trial. Foremost, cisplatin should be part of a standard-of-care regimen for the
target cancer in question. Among the cancers in which cisplatin is indicated for treatment are
head and neck cancer, non-small cell lung cancer (NSCLC), ovarian cancer, and testicular
cancer.61,62,63,64 Since Adherex was unable to identify a controlled comparative trial
assessing the role of cisplatin, its precise contribution to the response rates in polytherapy is
difficult to estimate. However, marked improvements in response and survival occurred with
the introduction of platinum agents. Based on discussions with several prominent
oncologists, the prevalent opinion is that platinum agents make a major contribution.
Testicular cancer responds very well to platinum-containing chemotherapy.65,66 Complete
remission approaches 85%90% of patients, progression-free survival at one year ranges
between 75%90% of patients, and one- and three-year survival rates may exceed 90% of
patients. Unfortunately, other cancers respond less well. In ovarian cancer, three-year
complete response has been estimated at 30%40% of patients, with median time to
progression-free survival ranging between 11.515.5 months and overall survival about
30 months.67 Other studies with different routes of administration and stages of disease
calculate a range of median survival at 4165.5 months.68,69
Response to platinum-containing chemotherapies in head and neck cancers is also mediocre.
At one year, progression-free survival (PFS) has been reported to be 31%48% of patients,

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26 September 2011

and overall survival (OS) at two years was 55%72% of patients.70,71 In a recent review of
treatments for head and neck cancer, median progression-free survival ranged from 8.255
months depending on regimens, and median overall survival was 14.572 months.72 While
clinical response rates to chemoradiotherapy are high and do not require the prolonged
observation required of OS or PFS, they are less valid indicators of clinical benefit and
reflect the great and probably dominant impact of radiation, for which cisplatin is a
radiosensitizer, not the primary therapeutic agent.
From the practical viewpoint of conducting a study, NSCLC might be the most accessible
tumor type. NSCLC is by far the most common cancer and affects both genders. Over
200,000 persons are diagnosed each year in the United States.73 However, response to
cisplatin-containing therapies is the poorest of the four cancers for which platinum
chemotherapy plays a central role. After platinum-containing chemotherapy, survival at one
year usually does not exceed 40% of patients,74,75,76 although higher rates have also been
reported.77 Median survival times are usually less than one year.75,78 These results derive
from use of multiple chemotherapeutic agents.
Thus, despite a large patient population, the relatively poor response of NSCLC to cisplatin
creates difficulties in conducting a non-inferiority trial to detect a tumor protection effect of
STS. The large sample size that such a study would require is out of proportion to any riskbenefit effect for the NSCLC population.
Risk-benefit is a serious consideration for an adult tumor protection protocol. The risk would
be easily identified in consent documents by stating the purpose of the study. Since the
primary endpoint would be tumor protection, patients with NSCLC would be unlikely to
enroll in the trial, despite potentially important benefits such as reduced nephrotoxicity.
Thus, both inherent design issues and lack of study attractiveness independently are
challenges to investigators and patients.
Can practical, scientific, and risk-benefit issues be resolved by examining the other end of
patient-response spectrum to platinum chemotherapy patients with testicular cancer with a
response rate of 90% or more? Such a high, consistent response lends itself to trial design
with a precise statistical estimation of sample size and assumptions of tumor protective
effect. In this case, practicality fails because testicular cancer is an uncommon cancer. Aside
from affecting only men, testicular cancer has a global incidence of 1.5/105 compared to that
of lung cancer of 35.5/105. The distribution of testicular cancer varies among ethnicities; in
the Unites States from 19732004 the incidences per 100,000 men were 5.4 white, 0.95
black, and 2.05 Asian.79 In the United Sates in 2010, there were only 8250 newly diagnosed
cases.80 Participation of testis cancer patients in trials is likely to be better than for other
adult cancers because of fewer medical complications, the availability of curative treatment
and consequently greater likelihood of patient referral to an academic referral center.
However, treatment for most testis cancer patients at normal risk is standardized and can be
given in the community. Therefore, a minority of newly diagnosed men with testicular
cancer would likely be offered enrollment into a trial.

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26 September 2011

Beside the problem of few testicular cancer patients, a tumor protection trial has other
difficulties. Below we have drafted a summary sketch of a placebo-controlled, noninferiority design that would be necessary to demonstrate the lack of tumor protection of STS
and provided sample size calculations in Table 5-1:
Primary endpoint: Survival at one year. Survival is estimated to range between
90%98%81
Cisplatin is assumed to produce between 40%60% of the overall treatment effect of the
triple therapy regimen.
The non-inferiority margins to be evaluated are 5% and 10% of the cisplatin contribution.
Treatment Regimen: 3 cycles per 3 weeks
o Cisplatin 20/mg/m2 Days 15
o Bleomycin 30 IU Days 1, 8, 15
o Etoposide 100 mg/m2 Days 1582
Sodium thiosulfate (20g/m2) or placebo administered 6 hours after each dose of cisplatin.
Table 5-1.

Sample Size Calculations (N per Arm) for Non-Inferiority Study


of Cisplatin-Containing Regimen

Cisplatin Contribution

Overall Standard Response

Standard Plus STS Response

10% NI

5% NI

40%

95%

95%

517

2066

50%

95%

95%

331

1322

60%

95%

95%

230

918

Note: Cisplatin regimens with and without STS using one-sided alpha = 0.025 with 80% power
Attachment 2 includes complete sample size calculations

For example, when the sample size in each group is 331, a two-group large-sample normal
approximation test of proportions with a one-sided 0.025 significance level will have 80%
power to reject the null hypothesis that the test and the standard are not equivalent (the
difference in proportions, pT - pS, is 0.048 or farther from zero in the same direction) in
favor of the alternative hypothesis that the proportions in the two groups are equivalent,
assuming that the expected difference in proportions is 0.000 and the proportion in the
standard group is 0.950.
Based on STS animal data, we predict that the difference in overall survival (i.e., tumor
protection) to be undetectable or very small.
We consider this design to accurately reflect the realities of a tumor protection trial in
testicular cancer patients. The expected survival rates are well established in the literature.
The dominant response of cisplatin within a three-drug regimen is an estimate derived from
discussions with several prominent oncologists. Given that only 8300 new cases of testicular
cancer were diagnosed in 2010, the sample sizes certainly represent a challenge. In the
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26 September 2011

context of the 2000 pediatric cancer patients who might be ultimately eligible to receive STS
for ototoxicity protection, the time and resources involved in an adult testicular cancer trial
require deliberation by investigators, regulators, and sponsors.
Aside from practical limitations of a testicular cancer trial, the risk-benefit for patients also
faces scrutiny similar to that in NSCLC. Given that response to existing platinum-based
chemotherapy is high and competing therapeutic protocols may offer promise of additional
benefits, what benefit exists for a testicular cancer patient to enroll in a tumor protection
trial? While hearing protection is important in this young adult population, it is not as critical
as it is in young children. To offer a trial whose primary question is whether the agent
reduces survival poses novel and uncomfortable issues of informed consent, both in the
clinical context and IRB review. Any clinical argument made to minimize the risk of
chemoprotection in an adult trial equally strongly undermines the rationale for requiring the
study. If it is safe enough to perform an ethical adult trial, why is it not safe enough to
administer to children, who may obtain a very important quality of life benefit? The same
justification needed for informed consent would apply to a testicular cancer patient expecting
a high response as to a patient with NSCLC with lower expectations animal data argue for
low risk of tumor protection with STS. The low risk of tumor protection does not appear to
satisfy a risk-benefit argument in favor of an adult trial.
Evaluation of agents to protect against toxicities of antitumor agents is not new to the
Agency or its advisory committees. A case in point is the meeting of the Oncologic Drug
Advisory Committee on March 12, 2003 to evaluate amifostine, an intracellular scavenger of
oxygen-free radicals.83 Amifostine was considered for protection against cisplatin
nephrotoxicity in adult cancer patients. The Agencys position at the time was that a noninferiority trial was necessary to show that amifostine did not have a tumor protective effect,
or, as one medical advisor stated, Why should the test drug protect the patient and not the
tumor?
The committee was unable to resolve design and other issues regarding a non-inferiority trial,
and eventually amifostine was not pursued for that indication. For cancers with low response
to cisplatin-containing regimens such as NSCLC and ovarian cancer, very large sample sizes
led to considerable discussion. The committees debated the nature of tumor response such as
survival, progression-free survival, and other sensitive indicators. The difficulty in ascribing
tumor response specifically to cisplatin in a multi-drug regimen was discussed but not
resolved since no robust study assessing the contribution of cisplatin existed among any
tumor types.
Testicular cancer was also discussed since it responds well to platinum-containing regimens
and thus might be conducted with fewer patients. One question involved acceptable margins.
Since margins define a level of tumor protection and directly relate to sample size, flexibility
was suggested. However, a clinically acceptable margin could not be defined, and concern
was raised about testing for tumor protection in a disease with such a high probability of
cure.

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We raise these generalities to put our proposal in context and not to compare directly
amifostine and STS. However, we distinguish STS because STS is being considered for
children not adults, is administered much later not before administration of
chemotherapeutics, acts extracellularly not intracellularly, and can be modeled for tumor
protection unambiguously in animals. Issues regarding implementation of a non-inferiority
trial have plagued the Agency, sponsors, and the medical community for ten years or more.
We all seek the means to answer the question of protection of the patient and not the tumor.

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CONCLUSION

Cisplatin and other platinum compounds are essential chemotherapeutic components for
many pediatric malignancies. Unfortunately platinum-based therapies at commonly used
doses and schedules cause ototoxicity in many patients, and are particularly harmful to the
survivors of pediatric cancer.
The clinical impact of platinum chemotherapy ototoxicity ranges from tinnitus and hearing
difficulty in older children and adolescents to impaired language acquisition in younger
children. Even minimal hearing loss in frequency ranges above 2 kHz increases a childs risk
for academic difficulty, social, and emotional problems, and fatigue in the learning
environment.28,35,84 In one study, 37% of public school children with minimal hearing loss
were held back one grade compared with only 3% of other students.85 Thus, cisplatin
ototoxicity is a common side effect with serious consequences, especially in children in
whom hearing loss profoundly affects quality of life. The impact of hearing loss in very
young children is devastating, since language development and general learning at that age
are critically dependent upon hearing.
STS has the potential to prevent chemotherapy-induced hearing loss and be the first available
agent approved for this condition. An often overlooked aspect of the use of STS to prevent
toxicity is preservation of prescribed doses of cisplatin in chemotherapeutic regimens. In
pediatrics, ototoxicity is usually dose-limiting. When children experience significant
ototoxicity, the cisplatin dose may be reduced or, more often, cisplatin may be eliminated
from the regimen. The efficacy of therapy in cisplatin-sensitive tumors may be affected by
dose reduction. If STS is able to prevent or reduce ototoxicity, children will be able to
receive prescribed dose of cisplatin, which could result in improved EFS/OS.
Two Phase III studies are ongoing. SIOPEL 6 began in October 2007 and COG ACCL0431
was initiated in June 2008. Combined enrollment is 152 children through August 2011. The
studies were expected to fully enroll within three years. However availability of eligible
patients fluctuates (some because of prior cranial irradiation) and more treating physicians
are needed. All of the institutional Principal Investigators support the studies and intend to
continue enrolling patients.
Based on the extensive use of STS for cyanide poisoning and in cancer treatments, the
historical safety data reveal no serious difficulties. The present studies intend to support the
hypothesis that in a group of cancer patients with high chance of cure it might be possible to
prevent ototoxicity and late sequelae and produce equivalent cure rate.
The Agency has questioned the potential for the antioxidant STS to react with cisplatin and
confer tumor protection. The Agency suggested that a non-inferiority trial will be necessary
in adult cancer patients to rule out that STS is tumor protective. As have other sponsors and
advisory groups, Adherex has evaluated the possibility of conducting such a trial and has
been unable to solve serious design and risk-benefit questions. To conduct a non-inferiority
trial in either pediatric and adult patients would require the cooperative groups (COG,

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SWOG, etc.) to prioritize the trial ahead of trials of new agents that could improve survival
(especially for NSCLC and pediatric malignancies like neuroblastoma and medulloblastoma).
Such prioritization is very unlikely.
Other problems include the significantly higher severity of cisplatin ototoxicity and its social
consequences in children compared to adults. In adults, hearing loss from noise and aging is
common and baseline hearing thresholds are a variable that influences ototoxicity risk. It is
very rare to find pre-existing hearing loss in pediatric cancer patients before starting therapy.
Ototoxicity risk is influenced more by age and cisplatin dose, and hearing loss is not the
dose-limiting toxicity in adults that it is in children.
In summary, should the results of COG Study ACCLL0431 be compelling, Adherex requests
that STS be considered for filing under accelerated approval. This would allow early access
to STS for the prevention of ototoxicity induced by platinum cancer chemotherapy in
pediatric patients, a serious condition with unmet medical need. Additional safety and
efficacy data to confirm the benefits of STS could be generated in the post marketing setting.
We welcome input from the Advisory Committee and the Agency.

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ATTACHMENTS

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Attachment 1.

26 September 2011

Comparison of SIOPEL 6 and COG ACCL0431


SIOPEL 6

COG ACCL0431

Trial

A Multi-Centre Open Label Randomized Phase III Trial of the


Efficacy of STS in Reducing Ototoxicity in Patients Receiving
Cisplatin Chemotherapy for Standard Risk Hepatoblastoma

A Randomized Phase III Study of STS for the Prevention of Cisplatin-Induced


Ototoxicity in Children

Design

Randomized, Open Label, Phase III clinical trial: 1:1


randomization between Cisplatin alone & Cisplatin + STS
infusion

Randomized, Controlled, Phase III clinical trial designed to assess the efficacy of
delayed STS infusion between Cisplatin alone & Cisplatin + STS infusion.
Patients to be randomized either to receive STS after each Cisplatin dose or not. The
randomization will be stratified by age (< 5 vs. 5 years) & duration of Cisplatin
infusion (< 2 vs. 2 hours).

Primary Objective

To assess the efficacy of STS to reduce the hearing impairment


caused by Cisplatin chemotherapy administered for Standard
Risk Hepatoblastoma

To assess the efficacy of delayed STS infusion between Cisplatin chemotherapy


(planned cumulative dose 200 mg/m2) for the treatment of newly diagnosed
hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, medulloblastoma, or
any other malignancy treated with cisplatin. It is hypothesized that there will be a 50%
relative reduction in the proportion of subjects with hearing loss in the STS-treated group
versus the control group.

Secondary
Objectives

To carefully monitor any potential impact of STS on


response to Cisplatin & survival
To assess the short- & long-term tolerability of the
combination of STS & Cisplatin
To prospectively evaluate & validate various biological,
radiological & pathological features of standard risk
hepatoblastoma for future risk adapted management
To investigate the effect of STS on the formation of
Cisplatin-DNA adducts
To prospectively collect patient DNA specifically for the
analysis of possible genetic factors that may contribute to
the development of treatment related to ototoxicity &
nephrotoxicity

Available for public disclosure without redaction

To compare the mean change in hearing thresholds for key frequencies between
the 2 randomized groups
To compare the incidence of Cisplatin-related Grade 3 & 4 nephrotoxicity &
Grade 3 & 4 cytopenia between the randomized groups
To monitor Event Free Survival & Overall Survival among the 2 randomized
groups
To evaluate the association of two key gene mutations (TPMT and COMT) with
the development of cisplatin-induced hearing loss

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SIOPEL 6
Primary Endpoint

Secondary
Endpoints

Rate of Brock 1 hearing loss determined after end of trial


treatment or at an age of at least 3.5 years, whatever is the later.
Conventional audiometry equipment to be used in all cases.
Rate of Brock grade 1 hearing loss after the end of trial
treatment or at an age of at least 3.5 years, whichever is
later
Response to preoperative chemotherapy
Complete resection
Complete remission
Event Free Survival
Overall Survival
Toxicity as graded by CTCAE v3
Long-term renal clearance

26 September 2011

COG ACCL0431
Rate of ASHA hearing loss determined 4 weeks and 12 months after last course of
1
Cisplatin. Conventional audiometry equipment to be used in all cases .
Response to preoperative chemotherapy
Complete remission
Event Free Survival
Overall Survival
Changes in sodium levels during study period
Long-term renal clearance

Patients

Approx. 102 evaluable patients 1 month 18 years old


(115 randomized patients)

135 randomized patients 118 years old

Recruitment

35 subjects per year - expected duration of recruitment period:


3.8 years

50 subjects per year expected duration of recruitment period: 3.0 years

Patient Source

Expected number of countries: up to 33, primarily Europe, but


also Japan, Asia, Australia and New Zealand

Expected number of countries 24, primary USA, but also Canada, Australia and
New Zealand

Subjects in this study will be co-enroll onto the COG observational cohort study of hearing assessment, ACCL05C1, ototoxicity will be evaluated by audiological assessments
that include conventional audiometry (all institutions) and measurement of otoacoustic emissions(OAE) and ultra-high frequency (UHF) audiometry (where available). UHF
audiometry and OAE may be early predictors of initial ototoxic changes in conventional audiometry.

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Briefing Document Pediatric Subcommittee of ODAC

SIOPEL 6
Inclusion Criteria

1 month 18 years old


Histologically confirmed newly diagnosed hepatoblastoma
Standard Risk Hepatoblastoma
Able to participate in the audiometry at the minimum
required quality standard
For females of child-bearing potential, a negative
pregnancy test prior to study treatment is required
Any patient who is of reproductive age should agree to use
adequate contraception for the duration of the trial.
Written informed consent, plus national/local ethics &
regulatory approval

Exclusion Criteria

High Risk Hepatoblastoma


Hepatocellular carcinoma
Treatment starting more than 15 days from written biopsy
report
Abnormal renal function
Any previous platinum based chemotherapy
Recurrent disease
Previous hypersensitivity to STS
Patient unable to follow the protocol for any reason

Available for public disclosure without redaction

26 September 2011

COG ACCL0431
118 years old
Newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma,
neuroblastoma, medulloblastoma, or other malignancy treated with cisplatin.
Chemotherapeutic plan that includes Cisplatin with a planned cumulative dose
200 mg/m2 with individual Cisplatin doses to be infused over 6 hour period
Not included on any other COG disease-related study
Performance status score of 50 on the Karnosky criteria for patients >16 years
of age & Lansky criteria for patients< 16 years of age
Not previously received platinum-based chemotherapy treatment
Previously received cranial irradiation prior to administration of systemic
chemotherapy provided normal hearing is documented at time of enrollment
Completion of hematopoietic stem cell transplant 6 month prior to enrollment
Normal audiometry results prior to treatment
Serum sodium levels within normal range for age
Adequate hematological functions for age
Adequate renal function for age
Adequate liver functions for age
Written informed consent, plus national/local ethics & regulatory approval
Women of childbearing age must have a negative pregnancy test
Females who are lactating must agree to stop breast feeding
Patients must not have a known hypersensitivity to STS or other thiol agents

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26 September 2011

SIOPEL 6
Trial Plan

Trial consists of the following phases:

Chemotherapy
Guidelines &
Treatment schedule

Histological confirmation of diagnosed hepatoblastoma


Pre-operative chemotherapy:
4 courses of Cisplatin, randomized 1:1 with or without
STS, every second week
Surgical removal of all remaining tumor lesions
Post-operative chemotherapy:
2 courses of Cisplatin, with or without STS, every second
week
Long-term follow-up

For all patients:


Pre-surgery: 4 courses on Day 1, 15, 29, and 43
Post-surgery: as soon as possible, but within 21 days:
2 courses on Day 1 and 15
Cisplatin:
For children > 10kg
- 80 mg/m2 IV infusion over 6 hrs
For infants & children 510kg
- 2.7 mg/kg IV infusion over 6 hrs
For infants < 5kg
- 1.8 mg/kg IV infusion over 6 hrs
For patients randomized to STS:
For children randomized to receive STS at Day 1, 15, 29 and 43
pre-surgery and day 1 and 15 post-surgery six hours after the
completion of Cisplatin infusion,
For children > 10kg
- 20 g/m2 IV infusion over 15 minutes
For infants & children 5-10kg
- 15 g/m2 IV infusion over 15 minutes
For infants < 5kg
- 10 g/m2 IV infusion over 15 minutes

Available for public disclosure without redaction

COG ACCL0431
Trial consists of the following phases:
Newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma,
neuroblastoma, medulloblastoma, or other malignancy treated with cisplatin
Cisplatin to be administered in accordance with disease specific cancer treatment
protocol in use without being specified in the study.
Hematopoietic stem cell transplant for high risk neuroblastoma patients
After each infusion of Cisplatin those randomized to STS therapy to receive an
infusion over 15 minutes
Long-term follow-up
For all patients:

Cisplatin:
To be administered in accordance with disease specific cancer treatment protocol in
use without being specified in the study. Cumulative dose 200 mg/m2 with individual
Cisplatin doses to be infused over 6 hour period, & when multiple doses of Cisplatin
are required there needs to be a 10 hour delay between the administration of STS & the
next days Cisplatin dose
For patients randomized to STS:
For children randomized to receive STS six hours each day after the completion of
Cisplatin infusion, 16 g/m2 IV infusion over 15 minutes or 533 mg per kg for patients
whose therapy protocol administers Cisplatin on a per kg basis due to young age or
small body size

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Briefing Document Pediatric Subcommittee of ODAC

26 September 2011

SIOPEL 6
Administration

Special Precautions

COG ACCL0431

Cisplatin:
Cisplatin in 0.9% sodium chloride. Suggested volume for
infusion over 6 hours:
- < 60 mg in 60ml
- 60 mg-120mg in 120ml
- > 120 mg in 240ml
STS:
Six hours post-Cisplatin:
- Dilute to a concentration of 125 mg/ml with Sterile Water
for Injection
- Infuse over 15 minutes
- Stop the Cisplatin hydration fluid for 15 minutes during the
STS infusion
- Restart the Cisplatin hydration immediately afterwards

Cisplatin:
To be administered in accordance with disease specific cancer treatment protocol in
use without being specified in the study.

There are no special precautions needed for safely administering


the drug. However, considerations prior to administration:

There are no special precautions needed for safely administering the drug. However,
considerations prior to administration:

Adequate anti-emetic therapy


Urea & electrolytes, particularly sodium, within normal
range for age.
Adequate hydration, which should be guaranteed by the
concomitant Cisplatin hydration.
Blood pressure within normal range for age.
A separate IV line is required as STS must not be mixed
with any other substance

Available for public disclosure without redaction

STS:
Six hours post Cisplatin:

Dilute each ml of the 25% STS with 1 ml of sterile Water for Injection (1:1
dilution) to a concentration of 125 mg/ml for direct administration
Infuse over 15 minutes
Stop the Cisplatin hydration fluid for 15 minutes during the STS infusion
Restart the Cisplatin hydration immediately afterwards

Adequate anti-emetic therapy


Urea & electrolytes, particularly sodium, within normal range for age.
Adequate hydration, which should be guaranteed by the concomitant Cisplatin
hydration.
Blood pressure within normal range for age.
A separate IV line is required as STS must not be mixed with any other
substance

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Briefing Document Pediatric Subcommittee of ODAC

SIOPEL 6

26 September 2011

COG ACCL0431

Determination of
Audio Testing

Brock

Brock (via COG ACCL05C1)


ASHA

Methods for
Audiologic
Assessment

OAE
Bilateral pure tone AC thresholds 0.5-8 kHz
(conventional,VRA, play audiometry)
ABR
TEOAEs
DPOAEs
Tympanometry

OAE
Bilateral pure tone AC threshold 0.58 kHz(conventional, VRA, play
audiometry)
Otoscopy
Tympanometry
Frequency specific ABR (if too young for evaluation with behavioral methods)
DPOAEs or TEOAEs
UHF (5 years & older)

Available for public disclosure without redaction

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Sodium Thiosulfate Injection, USP, 25%


Briefing Document Pediatric Subcommittee of ODAC

SIOPEL 6
Data Management

A web based, remote data entry (RDE) system has been


implemented through cooperation with CINECA, a non-profit
inter-university organization. Data quality control procedures are
applied within the RDE system.

Available for public disclosure without redaction

26 September 2011

COG ACCL0431
The COG web based, remote data entry (RDE) system has been implemented. Data
quality control procedures are applied within the RDE system.

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Briefing Document Pediatric Subcommittee of ODAC

Attachment 2.

Table 1:

Sample Size Calculations for Non Inferiority Study of Cisplatincontaining Regimen With/Without STS

Non-Inferiority (NI) Margins Based on Cisplatin Contribution to


Regimen

Cisplatin
Contribution

Overall
Standard
Response

40%

90%

.4

95%
50%

60%

Table 2:

26 Septembertober 2011

Cisplatin
Response

10% NI margin

5% NI margin

90=36%

-0.036

-0.018

.4

95=38%

-0.038

-0.019

98%

.4

98=39%

-0.039

-0.020

90%

.5

90=45%

-0.045

-0.022

95%

.5

95=47%

-0.048

-0.024

98%

.5

98=49%

-0.049

-0.025

90%

.6

90=54%

-0.054

-0.027

95%

.6

95=57%

-0.057

-0.029

98%

.6

98=59%

-0.059

-0.029

Sample Size (N per Arm) for Non-Inferiority Study of CisplatinContaining Regimen with and without STS using one-sided alpha=0.025
with 80% Power

Cisplatin
Contribution

Overall
Standard
Response

Standard plus
STS response

10% NI margin

5% NI margin

40%

90%

90%

1091

4361

95%

95%

517

2066

98%

98%

201

810

90%

90%

698

2791

95%

95%

331

1322

98%

98%

129

513

90%

90%

485

1938

95%

95%

230

918

98%

98%

89

356

50%

60%

Available for public disclosure without redaction

Page 45